This study explores the relationship between genetic polymorphisms of p53, p21, and CCND1, and the susceptibility of chromosomal damage induced by vinyl chloride monomer (CH(2)=CHCl, VCM). Besides gene polymorphisms, we detected the mRNA expression of p53, p21, and CCND1 in VCM-exposed workers and in a control group. One hundred and eighty-three workers occupationally exposed to VCM were investigated. Chromosome damage in peripheral lymphocyte was measured by cytokinesis-block micronucleus assay. The PCR-restriction fragment length polymorphism technique was applied to detect polymorphisms of p53, p21 (exon 2 and exon 3), and CCND1 genes (exon 4). The quantity of gene mRNA expression was detected by real-time PCR (SYBR Green I). Taking into account the effects of genetic polymorphisms, as well as demographic and habitual factors, Poisson regression analysis showed that the risk of chromosomal damage induced by VCM for individuals carrying the p53 intron 6 heterozygous and mutant homozygous genotype was 1.23 times larger (90% confidence interval, 1.01-1.51 P=0.0814), compared with those carrying wild-type homozygous genotypes. The p53 exon 4, intron 3, and intron 6 haplotype pairs of MMM/WWW (M, mutation allele; W, wild allele), and MWM/WWW were associated with increased frequencies of micronuclei. The p53 mRNA expression of VCM-exposed workers was significantly lower than that of nonexposed workers, but p21 mRNA expression in VCM-exposed workers was significantly higher than that of nonexposed workers. Our findings suggest that the p53 intron 6 polymorphism is one of the factors that potentially influence the frequency of micronuclei induced by VCM.